Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) display striking antineoplastic activity, although toxicity resulting from cyclooxygenase (COX) inhibition and incomplete protection from disease progression limits their use for cancer chemoprevention. Preliminary studies suggest that the mechanism for the chemopreventive activity of a highly efficacious NSAID, sulindac, does not require the inhibition of COX-1 or -2 and that cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition is responsible for its tumor cell growth inhibitory activity. We hypothesize that it is feasible to chemically modify sulindac to block COX inhibitory activity, while enhancing tumor cell growth inhibitory activity by increasing selectivity for cGMP PDE. In support of this hypothesis, we have synthesized a prototypic amide derivative of sulindac sulfide that does not inhibit COX-1 or -2, yet displays high potency to inhibit colon tumor cell growth and cGMP PDE in vitro. Sulindac sulfide amide (SSA) displayed adequate oral bioavailability and appeared to be less toxic than sulindac in mice. Using a xenograft model involving human colon tumor cells, SSA displayed comparable in vivo antitumor efficacy as sulindac, albeit at high dosages. These studies demonstrate the feasibility of uncoupling the COX inhibitory activity from the growth inhibitory activity of sulindac and supports further research to develop additional derivatives that are more potent and/or bioavailable than SSA. The following specific aims are proposed: 1) prepare a series of sulindac analogs to optimize for potency, selectivity, and oral bioavailability, 2) evaluate in vitro activity, 3) determine the mechanism of action and identify the target cGMP PDE isozyme, and 4) evaluate in vivo chemopreventive efficacy. Our goals are to identify a safe and efficacious derivative of sulindac for cancer chemoprevention and to critically test the hypothesis that cGMP PDE is a target for cancer chemoprevention. This multidisciplinary research proposal is anticipated to result in a new drug candidate for cancer chemoprevention, and in particular, patients with familial or sporadic adenomatous polyposis who are at high risk of disease progression. Project Narrative Nonsteroidal anti-inflammatory drugs (NSAIDs) display striking cancer chemopreventive activity, although toxicity resulting from cyclooxygenase (COX) inhibition and incomplete efficacy limits their clinical use for patients at moderate to high risk of disease progression. Preliminary studies suggest that the mechanism for the antineoplastic activity of sulindac does not require COX inhibition and that cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition is responsible for its tumor cell growth inhibitory activity. We hypothesize that it is feasible to chemically modify sulindac to block COX inhibitory activity, while enhancing tumor cell growth inhibitory activity by increasing selectivity for cGMP PDE. Our primary goal is to identify a novel sulindac derivative as a clinical candidate for patients with either familial or sporadic adenomatous polyps who are at high risk of disease progression. A secondary goal is to critically test the hypothesis that cGMP PDE is a target for cancer chemoprevention and involved in carcinogenesis. This multidisciplinary research proposal may lead to a novel strategy for colon cancer chemoprevention.